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EUROPEAN

COMMISSION

ENTERPRISE AND INDUSTRY DIRCTORATE-GENERAL

Consumer

goods

Pharmaceutcals

Brussels,

2-5

November 2008 (rev.)

Eudralex

The Rules

Governing

Medicinal

Products

in

the

European

Union

Volume 4

EU

Guidelines to

Good

Manufacturing

Practice

Medicinal Products for Human

and

Veterinary Use

Annex

I

Manufacture of

Sterile

Medicinal

Products

(corrected

versionl

Please

note

correction on the

implementation

of

provisions

for

capping of

vials

1

Note:

Provisions

on

capping of

vials should be

implemented

by

0l March

20I0.

Document

History

Previous version dated 30 May 2003, in operation

since

Septernber

2003

Revision to align classification

table

of clean rooms, to

include

guidance

on media simultations, bioburden

monitoring and

capping

of

vials

November

2005 to

Decernber

2007

Date

for

coming

into

operation

and superseding

01 March 2009'

Commission Europenne,

B-1049 Bruxelles / Europese Commissie,

B-1

049 Brussel

-

Belgium- Telephone:

(32-2)

299 11

11

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ANNEX

1

MANUFACTURE

OF STERILE

MEDICINAL PRODUCTS

Principle

The manufacture

of sterile

products

is

subject

to special

requirements

in

order

to minimize

risks

of microbiological

contamination,

and

of

partculate

and

pyrogen

contamination.

Much

depends

on

the

skill, training

and attitudes

of

the

personnel

involved.

Quality

Assurance

is

particularly

important,

and

this

type of

manufacture

must

strictly

follow

carefully established

and validated methods

of

preparation

and

procedure.

Sole

reliance

for

sterility or other

quality

aspects

must not be

placed

on

any

terminal

process

or

finished

product

tesl.

Note:

This

guidance

does

not lay

down

detailed

methods for determining the

rnicrobiological

and

particulate

cleanliness

of

air, surfaces

etc.

Reference

should

be

made to

other

documents such

as

the EN/ISO

Standards.

General

I

-

The

manufacture

of

sterile products should be carried

out

in

clean

areas

entry

to

which

should be through airlocks

for

personnel

and/o

for

equipment and materials. Clean

areas

should be

maintained

to

an appropriate

cleanliness standard and

supplied

with air which

has

passed

through

filters

ofan

appropriate

efficiency.

2.The

various

operations of

component

preparation, product

preparation

and

filling

should

be

carried out

in

separate areas within

the clean area,

Manufacturing

operations

are divided

into

two

categories,

firstly

those

where the

product

is

terminally sterilised,

and secondly

those

which

are

conducted aseptically

at some or all

stages.

3.

Clean

areas

for the manufacture

of

sterile

products

are

classified

according

to

the

required

characteristics

of the enviroument.

Each manufacturing

operation

requires

an

appropriate

environmental

cleanliness

level

in

the

operational

state

in

order

to

minimise the risks

of

particulate

or

microbial

contamination

of the

product

or

materials being

handled.

In order

to

meet

"in

operation"

conditions

these

areas

should

be

designed

to

reach

certain

specified

ai-cleanliness

levels

in

the

"at

rest"

occupancy

state.

The

"at-rest"

state

is the

condition where

the

installation

is installed and operating, complete

with

production

equipment but

with

no operating

personnel present.

The

"in

operation" state

is

the

condition

where the installation

is

functioning in

the

defined operating

mode

with

the specified

number

of

personnel

working.

The

"in

operation" and

"at

rest"

states

should be defined

for

each clean

room or

suite

ofclean

rooms.

For

the

manufacture

of

sterile

medicinal

products

4

grades

can

be distinguished.

Grade

A:

The local zone for high risk operations, e.g.

filling zone,

stopper

bowls,

open

ampoules and vials,

making

aseptic

connections.

Normally

such conditions

are

provided

by a

laminar

air

flow

work

station.

Laminar air

flow

systems should

provide

a

homogeneous

air

speed

in

a

range

of

0.36

-

0.54 m/s

(guidance

value)

at the

working

position

in open clean

room

applications.

The

maintenance of

laminarty should be demonstrated

and

validated.

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A

uni-directional air

flow

and

lower velocites

may

be used

in

closed

isolators

and

glove

boxes.

Grade

B: For

aseptic

preparation

and

filling, this

is

the

background

environment

for the

grade

A zone.

Grade

C and

D:

Clean

areas for

carrying

out

less

critical stages

in

the

manufacture

of

sterile

products.

Clean

room

and

clean

air device classification

4.

Clean

roorns

and

clean air devices

should

be classified

in accordance

with

EN

ISO

14644-

l. Classification should

be clearly differentiated

from operational

process

environmental

monitoring.

The maximum

permitted

airborne

particle

concentration

for

each

grade is

given

in

the

following

table.

5.

For

classification

purposes

in

Grade

A zones,

a

minimum sample

volume

of

lmt should

be

taken

per

sample

location.

For

Grade

A

the airbome

particle

classification

is ISO

4.8

dictated

by

the

limit for

particles

15.0

rm.

For Grade

B

(at

rest) the airborne

particle

classification

is

ISO 5 for

both

considered

particle

sizes. .

For

Grade

C

(at

rest &

in

operation)

the

airborne

particle

classification

is ISO

7

and

ISO I

respectively.

For

Grade

D

(at

rest) the

airborne

particle classification

is

ISO

8.

For

classifcation

purposes

EN/ISO

14644-l

methodology

defines

both the

minimum

number

of sarnple

locations

and the

sample size

based

on

the

class

limit of the

largest considered

particle

size and

the

method of

evaluation

of

the

data

collected.

6. Portable

particle

counters

with a short

length of sample

tubing

should

be

used

for

classification

purposes

because

of

the

relatively higher

rate

of

precipitation of

paficles

>5.0pm

in

remote

sampling

systems

with

long lengths

of

tubing.

Isokinetic

sample

heads

shall

be used

in

unidirectional

airflow systems.

7.

"ln

operation" classification

may

be

demonstrated

during

normal operations,

simulated

operations

or during

media

fills

as

worst-case

simulation

is

required

for

this.

EN

ISO

14644-2

provides information

on

testing

to

demonstrate

continued compliance

with

the

assigned

cleanliness classif,rcations.

Clean

room and clean air device

monitoring

8.

Clean

rooms and clean

air

devices

should be

routinely

monitored

in

operation

and

monitoring locations based on

a

formal

risk

analysis

study

and the

results obtained

during

classification

of

rooms

and/or

clean air devices.

9.

For

Grade

A

zones,

particle

monitoring

should

be

undertaken

for the

full

duration

of critical

processing,

including

equipment

assembly,

except where

justified

by

contaminants

in

the

the

the

Maximum

permitted

number of

particles

per m'

equal

to or

greater

than

the tabulated size

At

rest

ln operation

Grade

0.5

pm 5.0um

0.5

pm

5.0.rm

A

3

520 20

3

520

20

B

3 520

29

352 000

2900

C

352 000

2900

3 520 000

29

000

D

3

520 000

29 000 Not dehned

Not

defined

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process

that would damage

the

particle

counter

or

present

a

hazard,

e.g.

live

organisms

and

radiological hazards. In

such

cases monitoring during

routine

equipment set

up

operations

should be undertaken

prior

to

exposure

to

the

risk. Monitoring during

simulated

operations

should also be

performed.

The

Grade

A zone should be monitored

at

such a

frequency

and

with suitable sample size that all

intenentions, transient events and

any

system deterioration

would be

captured

and

alarms triggered

if

alert

lirnits

are

exceeded.

It

is

accepted

that

it

may

not

always

be

possible

to

demonstrate

low

levels of

5.0

pm

particles

at

the

point

of fill when

filling

is

in progress,

due

to

the generation

of particles or droplets from

the

product itself.

10.

It

is recommended that a similar system be used

for

Grade

B zones

although the sample

frequency may

be

decreased.

The

importance

of the

particle

monitoring

system should

be

determined by

the effectiveness

of the segregation between the adiacent Grade

A

and

B

zones.

The

Grade

B

zone

should

be monitoed at such

a frequency and with

suitable sample size that

changes

in levels

of

contamination and any system deterioration would be

captured

and

alarms

triggered

if

alert

limits are exceeded.

I

l.

Airborne

particle

monitoring

systems

may consist

of

independent

particle

counters;

a

nefwork

of

sequentially

accessed sampling

points

connected by manifold to a single

particle

counter; or

a

combinaton of the two.

The

system selected

must

be

appropriate

for

the

particle

size

considered.

Where remote sampling

systems are used,

the length

of

tubing

and

the

radii

of any bends

in

the tubing

must

be

considered

in

the

context

of

particle

losses

in

the

tubing.

The

selection of the

monitoring

system should take account of

any

risk

presented

by the

materials

used

in

the

manufacturing operation,

for

example those involving

live

organisms

or

radiopharmaceuticals.

12.The

sample sizes

taken

for monitoring

purposes

using

automated systems

will

usually

be a

fi"urction of

the sampling

rate

of

the system used.

It

is not necessary for the sample

volume

to

be the

same as

that used

for formal

classification

of clean

rooms

and clean air devices.

13.

In

Grade

A

and

B zones,

the

monitoring

of the

>5.0

rm

particle

concentration count

takes

on a

particular

signif,rcance

as

it

is

an important diagnostic tool

for

early detection of

failure.

The occasional indication

of

>5.0

rm

particle

counts

may

be

false

counts

due

to

electronic

noise,

stray

light,

coincidence, etc.

However

consecutive

or

regular

counting of

low

levels is

an

indicator of a

possible

contamination event

and should

be

investigated.

Such

events

may indicate

early

failure

of

the

IIVAC

system,

filling

equipment

failure

or

may

also

be diagnostic

of

poor practices

during

machine

set-up and

routine

operation.

14.

The

particle

limits

given

in

the table

for

the

"at

rest"

state should

be

achieved

after a

short

"clean

up"

period

of

15-20 minutes

(guidance

value)

in

an

unmanned state after

completion

of operations.

15. The monitoring

of

Grade C and

D

areas

in

operation should be

performed

in

accordance

with

the

principles

of

quality

risk

management. The requirements

and alerlaction

limits

will

depend

on the

nature

of

the operations carried out,

but

the

recommended

"clean up period"

should

be

attained.

I6.

Other

characteristics

such as temperature and

relative humidity

depend

on

the

product

and

nature

of the

operations

caried out.

These

parameters

should

not interfere with

the defined

cleanliness

standard.

17.

Examples

of

operations to be carried out

in the various

grades

are

given

in

the table below

(see

also

paragraphs

28

to

35):

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Grade

Examples

of operations

for

terminally

sterilised

products.

(see

paragraphs

28-

30)

A Filling

of

products,

when unusually

at

risk

C

Preparation

of solutions. when unusuallv

at

risk.

Filline

of

nroducts

D

Preparation

of solutions

and

comnonents for

subseouent

fillinc

Grade Examnles of ooerations

for

asentic

nrenarations.

lsee

narasranhs.

31-35)

A

Aseotic

preparation

and

fillins.

C

Preparation

of

solutions to

be

hltered.

D Handlins

of comoonents

after

washins.

18. Where

aseptic

operations are

performed

monitoring

should

be

frequent

using

methods

such as settle

plates,

volumetric

air and surface

sampling

(e.g-

swabs and

contact

plates).

Sampling

methods

used

in

operation should

not

interfere with

zone

protection. Results

from

monitoring

should be considered when

reviewing

batch documentation

for finished

product

release.

Surfaces

and

personnel

should be monitored

after

critical operations.

Additional

microbiological

monitoring

is also

required

outside

production

operations,

e.g.

after

validation of

systems, cleaning and sanitisation.

19.

Recommended

limits

for

microbiological monitoring of clean

areas

during

operation:

Notes

(a)

These

are average values.

(b)

Individual

settle

plates

may

be exposed

for

less

than

4

hours.

20. Appropriate

alert

and action

limits

should

be

set

for

the

results of

particulate

and

microbiological monitoring. If these

limits

are

exceeded

operating

procedures

should

prescribe

corrective

action.

Isolator technology

21.

The

utilisation of

isolator

technology to

minimize human

interventions

in

processing

areas

may

result in

a

significant

decrease

in

the risk

of

microbiological

contamination

of aseptically

manufactued

products

from

the

environment. There

are

rnany

possible

designs

of

isolators

and

transfer devices,

The isolator

and the background

environrnent

should be

designed

so

that

the

required

air

quality

for

the

respective

zones

can

be

realised.

Isolators are constructed

of

various

materials more

or

less prone

to

puncfure

and leakage.

Transfer

devices

may

vary

from

a single door to double door designs to

fully

sealed systems

incorporating

sterilisation

mechanisms-

Recommended

limits

for

microbial

contamination

(a)

Grade air sample

cfu/m3

setfle

plates

(diameter

90

mm)

cfu/4

hours

(b)

contact

plates

(diarneter

55

mm)

cfir/plate

glove

print

-5

fingers

cfu/glove

A

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22.The

transfer of

materials into

and out of

the

unit

is

one

of

the

greatest

potential

sources

of

contamination.

ln

general

the

area

inside the isolator

is

the

local zone

for high

risk

manipulations,

although

it

is

recognised that laminar

ai

flow

may

not

exist

in

the working

zone

ofall such devices.

23.The

air classification

required

for

the background

environment

depends

on

the

design

of

the isolator

and

its

application.

It

should be

controlled

and

for

aseptic

processing

it

should

be

at least

grade

D.

24. Isolators should be

introduced

only after appropriate

validation. Validation should

take

into

account

all

critical

factors

of

isolator

technology,

for

example

the

quality

of the air

inside

and outside

(backgroturd)

the

isolator,

sanitisation of the

isolator, the iransfer

process

and

isolator

integrity.

2-5. Monitoring

should

be

carried out

routinely and

should

include frequent leak testing

of

the

isolator

and

glove/sleeve

system.

Blow/filUseal

techno

logy

26. Blowlftll/seal

units are

purpose

built

machines

in

which, in one continuous

operation,

containers are

formed

from

a

thermoplastic granulate,

filled

and

then

sealed,

all

by

the

one

automatic

machine. Blow/fill/seal

equipment used

for aseptic

production

which

is fitted with

an

effective

grade

A

air

shower

may

be

installed

in

at

least

a

grade

C environment,

provided

that

grade

A/B

clothing

is

used.

The

environment should

comply with the

viable

and

non

viable

limits

at

rest

and the viable

limit

only

when

in

operation.

Blow/fill/seal

equipment

used

for

the

production

of

products

which

are

terminally

sterilised should

be

installed

in

at

least a

grade

D

environment.

27.

Because

of this special

technology

particular

attention

should

be

paid

to,

at

least the

following:

.

equipment

design and

qualification

o

validation

and

reproducibility of

cleaning-in-place

and

sterilisation-in-place

.

background clean

room environment

in

which the

equipment

is

located

.

operator training and

clothing

o

interventions in

the

critical

zone

of

the equipment

including

any aseptic

assembly

prior

to the commencement of

filling.

Tenninally sterilised

products

28. Preparation

of components

and

most

products

should be done

in

at

least

a

grade

D

environment

in order to

give

low

risk

of

microbial

and

particulate

contamination, suitable

for

filtration

and

sterilisation. Where the

product

is

at a

high

or

unusual risk of

microbial

contamination,

(for

example, because the

product

actively supports

microbial

growth

or

must

be

held for

a

long

period

before

sterilisation or

is

necessarily

processed

not

mainly in

closed

vessels),

then

preparation

should be

carried out in

a

grade

C environment.

29. Filling of

products

for

terminal sterilisation should be carried

out

in at

least

a

grade

C

environment.

30. Where

the

product

is

at

unusual

risk

of

contamination

from

the

environment,

for

example

because

the

filling

operation

is

slow or the

containers ae

wide-necked or are

necessarily

exposed

for

more

than a

few

seconds

before sealing, the

filling

should

be

done

in

a

grade

A

zone

with

at

least

a

grade

C background.

Preparation

and

frlling

of

ointments, creams,

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suspensions

and emulsions should

generally

be carried

out

in

a

grade

C

environment

before

terminal

sterilisation.

Aseptic

preparation

31. Components after

washing

should

be

handled in at

least

a

grade

D

environment.

Handling

of

sterile starting

materials

and

components,

unless

subjected

to sterilisation

or

filtration

through

a

micro-organism-retaining filter

later in

the

process,

should

be done

in a

grade

A

environment

with

grade

B

background.

32.Preparation

of

solutions

which are

to

be sterile

filtered

during

the

process

should

be

done

in

a

grade

C environment;

if not fltered, the

preparation

of

materials

and

products

should

be

done

in

a

grade

A

environment

with a

gtade

B

background.

33. Handling and

filling

of aseptically

prepared

products

should

be done

in

a

grade

A

environment

with

a

grade

B

background.

34.

Prior

to the completion

of

stoppering,

transfer

of

partially

closed

containers,

as

used

in

freeze

drying

should

be done

either

in

a

grade

A

environment

with

grade

B

background

or

in

sealed

transfer trays

in

a

grade

B

environment.

35. Preparation and

filling

of

sterile ointments,

creams,

suspensions

and

emulsions

should

be

done

in

a

grade

A

environment,

with

a

grade

B

background,

when the

product

is

exposed

and

is

not

subsequently

filtered.

Personnel

36. Only the

minimun number

of

personnel

required

should

be

present

in

clean areas;

this

is

particularly

important

during

aseptic

processing.

Inspections

and controls

should

be

conducted outside the clean

areas

as far as

possible.

37. All

personnel

(including

those concerned

with cleaning

and

maintenance) ernployed

in

such

areas

should receive regular

training in

disciplines relevant to the correct manufacture

of

sterile

products.

This training should

include

reference to

hygiene and

to the basic

elements

of

microbiology. When

outside

staff

who

have

not received such

training

(e.g.

building

or

maintenance contractors)

need

to be brought

in,

particular

care should

be taken

over

their

instruction

and supervision.

38. Staff who

have

been engaged

in the

processing

of animal

tissue

materials

or

of

cultures of

micro-organisms other than

those used

in

the

current

manufacturing

process

should

not

enter

sterile-product

areas unless

rigorous

and

clearly defined

entry

procedures have been

followed.

39.

High

standards of

personal hygiene

and

cleanliness

are essential.

Personnel

involved in

the manufacture

of sterile

preparations

should

be

instmcted

to

report any condition

which

may

cause

the

shedding

of

abnormal

nurnbers

or

types

of

contaminants;

periodic

health

checks

for

such

conditions are desirable.

Actions

to

be taken

about

personnel

who could

be

introducing

undue

microbiological

hazard should

be decided

by a

designated

compeient

person.

40. Wristwatches,

make-up and

jewellery

should

not

be

worn

in

clean

areas.

41.

Changing

and

washing

should

follow

a

written

procedure

designed

to

minimize

contamination

of clean area clothing

or carry-through

of contaminants

to

the

clean areas.

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42. The

clothing

and

its

quality

should be appropriate

for

the

process

and

the

grade

of the

working area.

It

should

be

worn

in

such

away as

to

protect

the

product

from

contamination.

43.

The

description

of clothing

required

for

each

grade

is

given

below:

o

Grade

D: Hair

and,

where

relevant,

beard should be

covered.

A

general

protective

suit

and appropriate

shoes

or

overshoes

should be

worn. Appropriate

measures

should

be

taken

to avoid

any

contamination coming

from

outside

the clean

area.

.

Grade C:

Hair

and

where

relevant

beard and

moustache should be

covered.

A

single

or

two-piece trouser suit,

gathered

at

the wrists and

with high

neck

and

appropriate

shoes

or

overshoes should

be

worn.

They

should shed

virtually no fibres or

particulate

matter.

Grade

A/B:

Headgear

should totally

enclose

hair

and,

where

relevant, beard and

moustache, it

should be tucked

into

the

neck of the suit;

a face

mask

should

be

worn

to

prevent

the

shedding of droplets.

Appropriate sterilised,

non-powdered

rubber

or

plastic gloves

and sterilised

or

disinfected

footwear

should

be

worn.

Trouser-legs

should

be

tucked inside

the

footwear and

garment

sleeves

into

the

gloves.

The

protective

clothing

should

shed virnally

no

fibres

or

particulate

mafter

and

retain

particles

shed

by the body.

44.

Outdoor clothing

should

not

be brought

into changing

rooms

leading

to

grade

B

and

C

rooms.

For

every

worker

in

a

grade

A/B

area,

clean

sterile

(sterilised

or adequately sanitised)

protective

garments

should be

provided

at

each

work session. Gloves

should be

regularly

disinfected

during

operations.

Masks

and

gloves

should

be changed at

least

for

every

working

session.

45.

Clean

area

clothing

should be cleaned and

handled

in

such

a

way

that

it

does

not

gather

additional

contaminants which

can

later

be

shed.

These

operations

should

follow written

procedures.

Separate

laundry

facilities for

such

clothing

are

desirable.

Inappropriate treatment

of clothing will

damage

fibres

and

may

increase the

risk

of

shedding

of

particles.

Premises

46.In

clean areas,

all

exposed

surfaces

should be smooth,

impervious and

unbroken

in

order

to

minimize

the

shedding

or

accumulation

of

particles

or

micro-organisms

and

to

permit

the

repeated

application

of

cleaning agents,

and

disinfectants

where

used.

47. To reduce

accunulation

of

dust and

to

facilitate

cleaning

there should

be

no

uncleanable

recesses

and a

minimum

of

projecting

ledges,

shelves,

cupboards

and

equipment.

Doors

should be designed to avoid those uncleanable

recesses;

sliding

doors

may

be

undesirable

for

this

reason.

48. False

ceilings

should be

sealed

to

prevent

contamination

from the space

above them.

49. Pipes

and

ducts

and

other

utilities

should be

installed so

that

they

do

not

create

recesses,

unsealed openings and surfaces which

are diffrcult

to clean.

50.

Sinks and drains should be

prohibited

in

grade

A/B

aeas

used

for

aseptic

manufacture.

In

other aeas air

breaks should

be fitted

between

the machine or sink and

the

drains.

Floor

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drains

in

lower

grade

clean

rooms should be

fitted

with

traps or

water

seals

to

prevent

back-

flow.

51.

Changing rooms should

be designed

as

airlocks

and

used

to

provide

physical

separation

of

the

different stages

of changing and

so

minimize

microbial

and

particulate

contamination

of

protective

clothing. They

should

be flushed effectively

with

filtered

air.

The final stage of

the

changing

room

should,

in

the

at-rest

state,

be the

same

grade

as

the area

into

which

it

leads.

The use

of

separate

changing

rooms

for

entering

and leaving

clean

areas

is

sometimes

desirable.

In

general

hand

washing

facilities

should be

provided

only

in

the

first

stage

of the

changing rooms.

52. Both

airlock

doors should

not

be

opened

simultaneously-

An

interlocking

system

or

a

visual

and/or

audible

warning

system

should

be

operated

to

prevent

the opening

of

more

than

one

door

at

a

time.

53.

A

f,ltered

air

supply should

maintain

a

positive

pressure

and

an air

flow

relative

to

surrounding

areas

of a

lower

grade

under

all

operational

conditions

and should

flush the

area

effectively.

Adjacent rooms

of

different

grades

should

have a

pressure

differential

of

l0

-

l5

pascals

(guidance

values).

Particular

attention

should

be

paid

to

the

protection

of

the

zone

of

greatest

risk,

that

is,

the immediate environment

to which

a

product

and cleaned components

which

contact the

product

are

exposed.

The various

recomlnendations

regarding air supplies

and

pressure

differentials

may need

to

be

rnodified where

it

becomes

necessary

to contain

some

materials,

e.g.

pathogenic,

highly toxic,

radioactive or

live

viral

or bacterial

materials or

products.

Decontamination

of

facilities

and treatment

of air

leaving

a clean

area

may be

necessary for

some

operations.

54.

It

should

be

dernonstrated that air-flow

patterns

do

not

present

a contamination

risk,

e.g.

care should

be

taken

to ensure

that

air

flows

do

not distribute

particles

from a

particle-

generating person,

operation

or

machine to

a

zone of

higher

product

risk.

55. A

warning

system should

be

provided

to

indicate

failure

in

the

air

supply.

Indicators of

pressure differences

should

be

fitted

between

areas

where

these

differences

are important.

These

pressure

differences should

be

recorded regularly

or otherwise

documented.

Equipment

56. A

conveyor

belt

should not

pass

through

a

partition

between

a

grade

A

or

B area and

a

processing

area of lower

air cleanliness,

unless the

belt

itself is continually sterilised

(e.g.

in a

sterilising tunnel).

57.

As

far

as

practicable

equipment,

fittings

and

services

should be

designed and

installed

so

that operations,

maintenance

and

repairs

can

be caried

out outside

the clean

area.

If

sterilisation is

required,

it

should

be

carried

out,

wherever

possible,

after

complete

reassernbly.

58.

When equipment

maintenance has

been

carried out

within

the clean area, ihe

area should

be cleaned,

disinfected and/or sterilised where

appropriate,

before

processing

recommences

if

the

required

standards of cleanliness and/or

asepsis

have

not been

maintained

during

the

work.

59. Water

treatment

plants

and

distribution

systems

should

be designed,

constructed

and

maintained so

as

to ensure

a

reliable

source

of

water

of

an

appropriate

quality.

They

should

not

be

operated

beyond their

designed

capacity.

Water

for

injections

should

be

produced,

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stored

and distributed

in

a

manner which

prevents

microbial

growth,

for

example

by

constant

circulation

at

a temperature above

70oC.

60. AII

equipment such as sterilisers, air

handling

and

filtration systems,

air

vent and

gas

filters,

water treatment,

generation,

storage

and distribution

systems

should

be subject

to

validation

and

planned

maintenance; their

return

to use should

be approved.

Sanitation

61.

The

sanitation

of

clean

areas

is

particularly

important. They

should

be cleaned

thoroughly

in

accordance

with

a

written

programme.

Where disinfectants are

used,

more than one type

should

be employed. Monitoring

should

be undertaken

regularly

in

order

to detect the

development

of resistant

strains.

62. Disinfectants

and

detergents

should be

monitored

for

microbial contamination;

dilutions

should be

kept in

previously

cleaned containers

and should only be stored

for

defined

periods

unless sterilised.

Disinfectants

and

detergents used

in Grades

A

and

B areas

should be

sterile

prior

to

use.

63. Fumigation

of

clean areas

may

be useful

for reducing

microbiological

contamination

in

inaccessible places.

Processing

64. Precautions

to

minimize

contamination should be

taken

during

all

processing

stages

including

the

stages

before sterilisation.

65. Preparations

of

microbiological

origin

should

not

be

made or

filled in areas

used

for the

processing

of other medicinal

products;

however,

vaccines

of dead

organisms

or of

bacterial

extracts

may

be

filled,

after

inactivation, in

the

same

premises

as other

sterile

medicinal

products.

66.

Validation of

aseptic

processing

should

include a

process

simulation

test using a

nutrient

medium

(media

fill).Selection

of

the

nuftient medium should

be

made

based

on

dosage

form

of

the

product

and

selectivity, clarity,

concentration and

suitability

for sterilisation

of the

nutrient

rnedium.

67.

The

process

simulation

test

should

imitate as

closely as

possible

the

routine aseptic

manufacturing

process

and

include all the critical subsequent

manufacturing steps.

It should

also

take

into

account

various

interventions

known

to occur during

normal

production

as well

as

\/orst-case

situations.

68.

Process simulation tests should be

performed

as

initial

validation

with

three

consecutive

satisfactory simulation

tests

per shift

and

repeated

at

defined intervals

and after

any

significant modification

to

the

HVAC-system,

equipment,

process

and

number of

shifts.

Normally

process

simulation tests should

be

repeated

fwice a

year per

shift and

process.

69. The nurnber

of

containers used

for media fills

should

be sufftcient to enable

a

valid

evaluation.

For

small batches, the

number

of

containers

for

media

fills

should at

least

equal

the size

of

the

product

batch.

The

target should be

zero

growth

and

the

following should

apply:

10

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o

When

filling

fewer than 5000

units,

no contaminated units should be detected.

.

When

filling 5,000

to

10,000

units:

a) One

(

I

)

contaminated unit

should

result in an

investigation, including

consideration of

a

repeat media fill;

b)

Two

(2)

contaminated

units

are considered

cause

for revalidation, following

investigation.

o

When

filling

more

than

10,000

units:

a)

One

(

l)

contaminated

unit

should result

in

an

investigation;

b)

Two

(2)

contaminated

units

are considered cause

for revalidation,

following

investigation.

70.

For

any run size, intennittent incidents

of

microbial contamination rxay be

indicative

of

low-level

contamination

that should be

investigated.

Investigation of

gross

failures

should

include

the

potential

impact

on

the sterility assurance

of

batches manufactured since the

last

successful

media

fill.

71.

Care should be

taken that any

validation

does not

compromise

the

processes.

72.

Water

sources,

water treatment

equipment and treated

water

should

be

monitored

regularly

for

chemical and

biological

contamination

and,

as appropriate,

for

endotoxins.

Records

should

be

maintained

of

the results

of

the

monitoring

and

of any

action

taken.

73.

Activities in

clean

areas

and

especially

when

aseptic

operations

are

in

progress

should

be

kept

to

a

minimurn

and

movement

of

personnel

should

be controlled and

rnethodical, to avoid

excessive shedding

of

particles

and organisms

due

to over-vigorous activity.

The

ambient

temperature and

humidity

should

not

be uncomfortably

high

because of the

nature of the

garments

worn.

74.

Microbiological

contamination of starting materials should be

minimal.

Specifications

should

include requirements

for

microbiological

quality

when

the

need

for

this

has

been

indicated

by

monitoring.

75.

Containers

and

mateials liable

to

generate

fibres

should

be minimised

in clean areas.

76.

Where

appropriate,

measures

should

be

taken to

minimize the

particulate

contamination

of

the end

product.

77.

Components, containers and equipment should

be

handled

after the

f,rnal

cleaning

process

in

such a

way

that they are

not

recontaminated.

78.

The interval

between the washing and drying and the sterilisation of

components,

containers

and equipment

as well

as between their sterilisation and

use

should

be

minimised

and

subject to a time-limit

appropriate to

the storage

conditions.

79.

The

time

between

the start of the

preparation

of

a

solution and

its

sterilisation

or

filtration

through a

micro-organism-retaining

filter

should

be

rninimised. There should be

a

set

maximum

pennissible

time

for

each

product

that takes

into

account

its

composition

and

the

prescribed

method

of

storage.

80. The

bioburden

should be

monitored before

sterilisation.

There should be

working

limits

on

contamination

immediately

before

sterilisation,

which are

related

io the

eff,rciency

of the

method

to be

used.

Bioburden

assay

should be

performed

on

each

batch

for

both

aseptically

11

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filled

product

and

terminally

sterilised

products.

Where overkill sterilisation

parameters

are

set

for

tenninally sterilised

products,

bioburden

might

be

monitored only

at

suitable

scheduled

intervals.

For

parametric

release

systems,

bioburden

assay

should

be

performed

on

each

batch

and considered as an in-process test. Where appropriate

the

level

of

endotoxins

should

be

monitored.

All

solutions,

in

particular

large volume

infusion fluids"

should

be

passed

through

a

micro-organism-retaining

filter,

if

possible

sited

immediately before

filling.

81.

Cornponents, containers, equipment and any other

article required

in

a clean

area

where

aseptic

work

takes

place

should

be

sterilised

and

passed

into the area through

double-ended

sterilisers

sealed

into

the

wall,

or by

a

procedure

which

achieves

the

same

objective

of

not

introducing

contamination.

Non-combustible

gases

should

be

passed

through

micro-organisrn

retentive filters.

82. The

efficacy of any

new

procedure

should

be

validated, and

the

validation verified

at

scheduled

intervals

based

on

performance

history

or

when any signihcant

change

is made

in

the

process

or

equipment.

Sterilisation

83.

All

sterilisation

processes

should

be

validated.

Particular attention should

be

given

when

the

adopted

sterilisation method

is not

described

in

the cuffent

edition

of

the

European

Pharmacopoeia,

or when

it

is

used

for

a

product

which

is not

a simple

aqueous

or oily

solution. Where

possible,

heat

sterilisation

is

the

method of choice.

In

any case,

the

sterilisation

process

must

be

in

accordance

with

the

rnarketing and

manufacturing

authorisations.

84. Before

any sterilisation

process

is

adopted

its

suitability

fo the

product

and

its

efficacy

in

achieving

the

desired

sterilising conditions

in

all

parts

of

each

type of

load

to

be

processed

should be

demonstrated

by

physical

measurements

and

by biological

indicators

where

appropriate.

The validity

of the

process

should be verified

at

scheduled

intervals,

at

least

annually, and whenever significant

modifications have been made

to

the

equiprnent.

Records

should

be

kept

of the

results.

85. For

effective sterilisation the whole of the

material

must

be

subjected

to

the required

treatment

and the

process

should be designed to ensure

that this

is

achieved.

86.

Validated

loading

patterns

should be established

for all sterilisation

processes.

87.

Biological

indicators

should be

considered as

an additional

method

for monitoring the

sterilisation.

They

should be stored and used

according to

the

manufacturer's

instructions,

and

their

quality

checked by

positive

controls.

If

biological

indicators are used,

strict

precautions

should

be

taken

to

avoid transfening

microbial

contamination

from them.

88. There should

be

a clear

means

of

differentiating

products

which

have

not

been sterilised

from

those which

have.

Each

basket,

tray

or

other carrier

of

products

or components

should

be clearly

labelled

with

the

material name,

its

batch

number

and

an

indication

of

whether or

not it

has

been

sterilised. Indicators such

as

autoclave tape

may be used, where

appropriate,

to

indicate whether or not

a

batch

(or

sub-batch) has

passed

through

a

sterilisation

process,

but

they

do

not

give

a

reliable

indication that

the

lot

is,

in fact,

sterile.

89.

Sterilisation

records

should

be available for

each

sterilisation

run. They should

be

approved as

part

of

the

batch

release

procedure.

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Sterilisation

by

heat

90. Each

heat

sterilisation

cycle

should be

recorded on

a

time/temperature

chart

with

a

sufficiently

large

scale or by

other appropriate

equipment

with suitable accuracy

and

precision.

The

position

of

the temperature

probes

used

for controlling

and/or

recording should

have

been determined

during the

validation,

and where applicable

also

checked against

a

second

independent

temperature

probe

located at the

same

position.

91.

Chemical

or

biological

indicators

may

also be

used,

but

should

not.

take the place

of

physical

measurements.

92.

Sufficient time

lnust

be allowed

for the

whole

of the

load

to

reach the

required

temperature before

measurement

of

the

sterilising

time-period

is

commenced.

This time

must

be

detennined

for

each

type

of

load to

be

processed.

93. After the high

temperature

phase

of a

heat sterilisation

cycle,

precautions

should

be

taken

against

contamination

of

a sterilised

load during cooling.

Any cooling

fluid or

gas

in

contact

with

the

product

should be sterilised

unless

it

can

be

shown

that

any

leaking container

would

not.

be approved

for

use.

Moist

heat

94. Both

temperature and

pressure

should

be

used to

monitor

the

process.

Control

instrumentation

should

normally

be

independent

of

monitoring

instrumentation

and

recording

charts. Where automated control and

monitoring

systems

are

used

for these

applications

they

should

be

validated to

ensure

that

critical

process

requirements

are

met.

System

and cycle

faults

should be

registered

by

the

system and observed

by the

operator.

The reading of

the

independent

temperature

indicator should be

routinely

checked

against

the chart

recorder

during

the

sterilisation

period.

For sterilisers

fitted with a

drain

at

the

bottorn

of

the

chamber.

it

may

also

be

necessary

to

record the

temperature

at this

position,

throughout

the

sterilisation

period.

There

should

be frequent

leak tests

on

the

chamber

when

a

vacuum

phase is

part

of

the

cycle.

95.

The

items

to

be

sterilised,

other than

products

in

sealed

containers,

should

be

wrapped

in

a

material which

allows

removal

of air

and

penetration

of

steam but

which

prevents

recontamination

after sterilisation.

All

parts

of

the

load

should

be

in contact

with

the

sterilizing agent

at

the

required

temperature

for

the

required time.

96.

Care should be

taken

to

ensure

that steam

used

for

sterilisation

is of suitable

quality

and

does

not

contain

additives

at

a

level

which

could cause

contamination

of

product

or

equipment.

Dry heat

97 .

The

process

used

should

include air circulation

within

the chamber

and

the

maintenance

of

a positive

pressure

to

prevent

the entry

of

non-sterile

air.

Any air

adrnitted

should

be

passed

through a

HEPA filter.

Where this

process

is also

intended

to

remove

pyrogens,

challenge

tests

using endotoxins should be

used as

part

of the

validation.

Sterilisation

by

radiation

98.

Radiation

sterilisation

is

used

mainly

for

the sterilisation

of

heat

sensitive

materials

and

products.

Many medicinal

products

and some

packaging

materials

are

radiation-sensitive,

so

this

method

is

permissible

only

when the absence

of

deleterious

effects

on the

product

has

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been confirmed experimentally.

Ultraviolet

iruadiation is not normally

an

acceptable

method

of

sterilisation.

99, During

the sterilisation

procedure

the

radiation dose should be

measured.

For

this

purpose,

dosimetry

indicators

which are

independent

of

dose

rate

should be

used,

giving

a

quantitative

measurement

of

the dose received

by the

product

itself.

Dosimeters

should

be

inserted

in

the

load

in

sufficient

nurnber

and

close

enough

together

to

ensure that

there

is

always

a dosimeter

in the irradiator.

Where

plastic

dosimeters

are

used they

should be used

within

the time-limit

of

their

calibration. Dosimeter

absorbances

should

be

read

within

a

shorf period

after

exposure

to radiation.

100.

Biological indicators may

be used as

an

additional control

101.

Validation

procedures

should

ensure

that

the

effects

of variations

in

density

of

the

packages

are

considered.

102. Materials handling

procedures

should

prevent

mix-up

between

irradiated and

non-

inadiated materials. Radiation

sensitive colour disks should

also

be

used

on each

package

to

differentiate befween

packages

which have been subjected to

inadiation

and

those

which

have

not.

103. The

total

radiation

dose

should

be administered

within a

predetermined

time

span.

Sterilisation with

ethylene

oxide

104.

This method

should

only

be used when no other

method is

practicable.

During

process

validation

it

should be

shown

that

there

is no

damaging

effect on the

product

and

that

the

conditions and time allowed

for

degassing

are

such

as

to

reduce

any

residual

gas

and

reaction

products

to defined

acceptable limits for the type of

product

or

material.

105.

Direct

contact between

gas

and microbial cells

is

essential;

precautions

should be taken

to

avoid the

presence

of

organisms

likely

to be enclosed

in material

such

as

crystals or dried

protein.

The

nature

and

quantity

of

packaging

materials

can

significantly

affect the process.

106. Before

exposure to the

gas,

materials

should be brought

into

equilibriun

with

the

hurnidity

and temperature

required

by

the

process.

The

time

required

for

this should

be

balanced against the

opposing

need

to

minimize

the

time before

sterilisation.

107. Each sterilisation

cycle should

be monitored

with suitable

biological

indicators,

using

the

appropriate

number

of

test

pieces

distributed

throughout

the load.

The inforrnation

so

obtained

should

form

part

of the batch

record.

108.

For

each

sterilisation cycle,

records

should

be

made

of

the time

taken

to

complete

the

cycle,

of

the pressure,

temperaftre

and

humidity

within

the chamber

during

the

process

and

of

the

gas

concentration and

of

the

total

amount of

gas

used.

The

pressure

and temperature

should

be

recorded throughout

the cycle on a chart.

The record(s) should

form

part

of

the

batch

record.

109.

After sterilisation,

the

load

should be stored

in

a

controlled

manner

under

ventilated

conditions

to allow residual

gas

and

reaction

products

to

reduce to the defined

level.

This

process

should

be

validated.

14

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Filtration

of

medicinal

products

which

cannot

be

sterilised

in

their

final container

I10.

Filtration

alone

is not

considered

sufficient

when sterilisation

in the

final

container

is

possible.

With

regard

to

methods

currently

available,

steam

sterilisation

is

to be

prefened.

If

the

product

cannot

be

sterilised

in the

final

container,

solutions

or

liquids

can

be

filtered

through

a

sterile

filter of

nominal

pore

size of

0.22 micron

(or

less),

or

with at

least

equivalent

micro-organism retaining

properties,

into a

previously

sterilised

container.

Such

filters

can

remove most bacteria

and

moulds,

but not

all

vimses

or

mycoplasmas. Consideration

should

be

given

to complementing

the

filtration

process

with some degree

of

heat

treatment.

I I

l.

Due

to the

potential

additional

risks of the

filtration

method

as

compared

with other

sterilization

processes,

a

second

filtration

via

a

further

sterilised

micro-organism

retaining

frlter, immediately

prior

to

filling, may be

advisable.

The final sterile

filtration should

be

carried out

as

close

as

possible

to the

filling

point.

I

12.

Fibre-shedding characteristics

of filters should

be

minimal.

113. The integrity

of

the sterilised

filter shoud

be

verified

before

use and should

be

confirmed

mmediately after use

by

an appropriate

method such

as

a bubble

point,

diffusive

flow

or

pressure

hold

test. The

time

taken

to

filter

a

known volume

of bulk

solution

and

the

pressure

difference

to

be

used

across

the

filter

should

be

detennined

during

validation

and any

significant

differences

from

this

during

routine

manufacturing

should

be

noted and

investigated. Results

of

these checks

should be

included

in the

batch

record.

The iutegrity of

critical

gas

and

air vent

filters

should

be confirmed

after

use.

The integrity of

other

filters

should

be

confirmed

at

appropriate

intervals.

I

14. The same

filter

should

not

be

used

for

more than one

working

day

unless

such use

has

been

validated.

I15. The

filter

should

not

affect

the

product

by

removal of

ingredients

from it

or by

release

of

substances

into

it.

Finishing

of sterile

products

1

16.

Partially

stoppered

freeze drying

vials

should

be

maintained under

Grade

A

conditions

at

all tirnes until

the stopper

is fully inserted.

117.

Containers

should be

closed

by appropriately

validated

methods. Containers

closed

by

fusion,

e.g.

glass

or

plastic

ampoules

should

be

subiect

to

100% integrity testing.

Samples

of

other containers

should be checked

for integrity according

to

appropriate

procedures.

118.

The

containe

closure

system

for aseptically

filled

vials is not fully integral until

the

aluminium cap

has

been

crimped

into

place

on the

stoppered

vial.

Crimping

of

the cap should

therefore

be

performed

as

soon

as

possible after

stopper

insenion.

l19.

As

the

equipmeni

used to crimp

vial

caps

can

generate large

quantities

of non-viable

particulates,

the

equipment should

be

located

at a

separate station

equipped

with adequate

air

extraction-

120.

Vial

capping

can be

undertaken

as an

aseptic

process

using

sterilised

caps

or as a clean

process

outside

the aseptic core.

Where

this

latter

approach

is adopted,

vials

should be

protected

by

Grade A

conditions

up

to

the

point

of

leaving the aseptic

processing

area,

and

thereafter

stoppered vials should

be

protected

with a Grade

A

air

supply

until

the

cap

has

been

15

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crimped.

121.

Vials

with

missing or displaced stoppers

should

be

re.jected

prior

to

capping.

Where

human

intervention

is required at the capping station,

appropriate

technology

should

be

used

to

prevent

direct

contact

with

the

vials

and to

minimise

microbial

contamination.

122. Restricted access barriers

and

isolators

may be benehcial

in

assuring

the

required

conditions

and

minirnising

direct

human

interventions

into the

capping

operation.

123.

Containers

sealed

under

vacuurn

should

be

tested

for

maintenance

of

that

vacuum after

an

appropriate,

pre-determined period.

124.

Filled

containers

of

parenteral products

should

be

inspected

individually

for

extraneous

contamination

or other

defects.

When inspection

is done

visually,

it should

be

done

under

suitable

and

controlled

conditions of

illumination

and background.

Operators

doing

the

inspection should

pass

regular eye-sight

checks,

with

spectacles

if

worn, and

be

allowed

frequent breaks

from

inspection. Where other

methods

of

inspection

are used,

the

process

should

be

validated and the

performance

of

the

equipment

checked

at

intervals.

Results

should

be

recorded.

Quality

control

125.

The

sterility

test applied to the

finished

product

should

only

be

regarded

as

the

last

in

a

series

of control

measures by which sterility

is assured.

The test

should

be

validated

for

the

product(s)

concerned.

126.In

those

cases

where

parametric

release has been

authorised,

special

attention

should

be

paid

to the

validation

and

the monitoring of the

entire

manufacturing

process.

I27. Samples

taken

for

sterility

testing

should be

representative

of the

whole of

the

batch, but

should

in

particular

include samples taken

from

parts

of the

batch

considered

to be

most at

risk of

contamination,

e.g.:

a.

for

products

which have been

filled

aseptically,

samples

should

include

containers

f,rlled

at

the

beginning

and

end

of the batch and after

any signifTcant

intervention,

b.

or

products

which

have

been

heat

sterilised

in

their

final

containers,

consideration

should

be

given

to

king

samples

from

the

potentially

coolest

part

of

the

load.